One of the common mechanisms in tumor formation is inactivation of one or more so-called tumor suppressor genes. Tumor suppressor genes (also known as “tumor-preventative” or “anti-tumor” genes) play an important role in the regulation of many basic cellular processes such as cell growth, division and proliferation, cell differentiation, and in communication of cells with other cells and with the extracellular environment. Inactivation of a tumor suppressor gene usually has devastating consequences on the regulation of cell growth within a specific tissues and usually results in tumor growth.
The selective growth advantage of tumor cells is often achieved by functional imbalance of opposing functions of tumor suppressors and oncogenes. Increased function of oncogenes such as growth factor receptors (such as epidermal growth factor receptor [EGFR] and platelet derived growth factor receptor [PDGFR]), or signaling molecule molecules (such as PI-3 kinase, Ras or Myc) promote proliferative potential of cells. When this is combined with decreased function of tumor suppressors and stabilized by inactivating mutations, cells may run out of protective responses such as apoptosis or senescence to balance the problem. Additional genomic instabilities including genetic events such as chromosomal translocations often stabilize effects of mutations subsequently leading to further amplification of anti-apoptotic, anti-senescence, and pro-proliferative signals.
The recently discovered TMPRSS2-ETS gene family chromosomal translocations and genetic alterations of tumor suppressor genes are the most common causes of neoplastic transformation leading to prostate tumorogenesis. Known prostate cancer tumor suppressor genes include Pten, p53, Rb, Nkx3.1, KLF6, and p27. However, it is clear that additional tumor suppressor genes are inactivated in primary prostate adenocarcinoma. According to the multi-hit/multi-gene hypothesis, several genes that control critical growth/survival/apoptotic pathways must be altered to lead to fully penetrant prostate cancer. For example, in mice, the loss of Pten must be accompanied by loss of p53 for progression from noninvasive to highly invasive tumors. Similar relationships have been found in other Pten double knockout models, which the second knockout gene is Nkx3.1 or p27.
A recently identified prostate cancer tumor suppressor gene is Hssh3bp1 which inhibits growth of prostate tumor cells in laboratory culture conditions. Expression of the Hssh3bp1 gene product, which is a protein, is lost in some patients with prostate tumors. Additionally Hssh3bp1 regulates the function of Abi1 kinase, which is implicated in malignant processes in leukemia. Inactivating mutations of Abi1/Hssh3bp1 have been found in primary tumors.
The successful development of novel therapies for cancer requires animal models which incorporate the unique anatomical and physiology characteristics of the target organ or tissue and appropriate stromal-tumor interactions and appropriate immunological responses. Genetically engineered mice provide these aspects. Tissue-specific developmental (through the use of developmentally regulated tissue-specific promoters driving Cre recombinase expression) or conditional (through the use of tamoxifen-responsive promoters driving Cre retroviral vectors) disruptions or overexpression of targeted genes resembles closely the mutation-driven inactivation of human tumor suppressors or activation of oncogenes, respectively, in situ. This allows evaluation of the process of tumorigenesis from early time points of gene inactivation, through early histopathological changes, and subsequently through tumor growth and metastases if such occur. The possibility of evaluation of different levels of tumor suppressor inactivation (through one- or two-allele knockouts, or production of hypomorphic, as well as knock-in mutant strains) allows understanding of both cell signaling pathways as well as production of specific preclinical models.